Colorectal cancer (CRC) is the third most common solid malignancy and the second leading cause of cancer mortality in the United States. Early-stage (stages 1 or 2) CRC represents over 40% of CRC cases. Most early- stage CRC patients receive curative surgery but not systematic chemo- or radiation therapy. This is partly due to the controversy regarding the benefits of these treatments on the long-term patient prognosis versus the significant side effects, physiological and psychological concerns, as well as the high costs associated with these treatments. Nonetheless, there are more than 20% of early-stage CRC patients who do not realize the expected benefits from the initial curative surgery. Many of these patients experience recurrence, progress to advanced stages, develop metastasis, and succumb to the disease. Therefore, in order to achieve the desired therapeutic efficacy and reduce the overall mortality in early-stage CRC patients, it is critical to accurately predict the prognosis of these patients, and identify those with high risk of recurrence and death for more intensive and targeted treatments. Emerging evidence has shown that microRNAs (miRNAs) are significantly implicated in the development and prognosis of CRC. However, whether miRNA signatures can be used to predict early-stage CRC prognosis has not been reported. Herein, we propose to conduct a two-stage (discovery and validation) pilot study in two well-characterized CRC populations in the Delaware Valley area, to systematically evaluate microRNA expression profiles on cancer-specific survival of early-stage CRC patients. A unique advantage of this study is that it will be conducted in a highly homogenous subgroup of early-stage Caucasian colon adenocarcinoma patients who received curative surgical resection but not systematic chemotherapy or radiotherapy, which will greatly minimize the confounding effects of these important variables that have largely hampered the identification of bona fide biomarkers in previous similar prognosis studies with more heterogeneous patient populations and clinical treatments. In addition, we will conduct extensive statistical analyses to characteriz the gene-gene and gene-environment interactions, as well as bioinformatics analyses to construct an in silico exploratory network of genes putatively targeted by the significant miRNAs. Finally, we will conduct additional validations of the identified significant miRNAs to test their generalizability in advanced-stage Caucasian patients and African American patients. This is a highly cost-effective study that leverages two well-characterized biorepository of CRC patient cohorts in the Delaware Valley area. This is one of the first systematic evaluations of miRNA signatures as predictors of early-stage CRC prognosis. This study is likely to provide proof-of-principle findings as the basis for us to launch larger-scale cohort studies in the future through our multi-institute domestic and international collaborations. With the combined more than 8000 already enrolled CRC patients, the cohort study will be able to offer more in-depth insights on the effects of multifaceted variables and markers that influence CRC prognosis. PUBLIC HEALTH RELEVANCE: MicroRNAs have been extensively implicated in colorectal cancer (CRC) etiology and clinical outcomes; however, it has not been reported whether microRNA expression signatures can predict the prognosis of early- stage CRC patients who only received curative surgery treatment. In this proposed study, we aim to identify tumor miRNA signatures that are associated with the cancer-specific survival of early-stage (stage 1 or 2) colon adenocarcinoma patients who received curative surgery but not systematic chemo- or radiotherapy, and test the generalizability of the identified significant miRNAs in advanced-stage and African American CRC patients. This study will help further stratify CRC patients and identify those with poor prognosis for more intensive and targeted modalities.